CDK inhibitor enhances the sensitivity to 5-fluorouracil in colorectal cancer cells

Int J Oncol. 2008 May;32(5):1105-10.


Thymidylate synthase (TS) is a dNTP synthetic enzyme and is also a target enzyme of 5-fluorouracil (5-FU). 5-FU is one of the anticancer agents most frequently used for the treatment of colorectal cancers. However, the clinical rate of response to its use as a single agent is not exceptionally high. Therefore, various combination chemotherapies have been devised. The elevated expression of TS in cancer cells is a serious obstacle in the clinical use of 5-FU. In the present study, TS expression was up-regulated by the knockout of the p21WAF1/CIP1 gene in human colorectal cancer HCT116 cells, suggesting that TS expression is mediated through the inhibition of cyclin-dependent kinase (CDK). Based on these findings, we tested whether the CDK inhibitor (CDKI) SU9516, acted as a suppressor of TS. SU9516 effectively reduced the expression of TS in a dose-dependent manner. Furthermore, the reduction of TS expression resulted in enhancement of the sensitivity to 5-FU in human colon cancer DLD-1 cells. Thus, SU9516 might be a promising compound for combination chemotherapy with 5-FU.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antimetabolites, Antineoplastic / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinases / antagonists & inhibitors*
  • Cyclin-Dependent Kinases / metabolism
  • Dose-Response Relationship, Drug
  • E2F Transcription Factors / genetics
  • E2F Transcription Factors / metabolism
  • Enzyme Repression
  • Fluorouracil / analogs & derivatives
  • Fluorouracil / pharmacology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Silencing
  • HCT116 Cells
  • Humans
  • Imidazoles / pharmacology
  • Indoles / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Thymidylate Synthase / antagonists & inhibitors*
  • Thymidylate Synthase / biosynthesis
  • Thymidylate Synthase / genetics
  • Transfection


  • Antimetabolites, Antineoplastic
  • Cyclin-Dependent Kinase Inhibitor p21
  • E2F Transcription Factors
  • Imidazoles
  • Indoles
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • SU 9516
  • Thymidylate Synthase
  • Cyclin-Dependent Kinases
  • Fluorouracil